Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

Julian Petersen, Shane C. Wright, David Rodríguez, Pierre Matricon, Noa Lahav, Aviv Vromen, Assaf Friedler, Johan Strömqvist, Stefan Wennmalm, Jens Carlsson, Gunnar Schulte*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

Original languageAmerican English
Article number226
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2017

Bibliographical note

Funding Information:
Nevin Lambert is kindly acknowledged for his scientific input and help in creating the stoichiometer construct. We thank Marin M. Jukic for his input in statistical analysis. The work was supported by grants from Karolinska Institutet, the Science for Life Laboratory, the Swedish Research Council (2007-2769, 2007-5595, 2011-2435, 2013- 5708, 2015-02899), the Swedish Cancer Society (CAN2011/690, CAN2014/659), the Knut & Alice Wallenberg Foundation (KAW2008.0149; 2008.0139), the Swedish Foundation for Strategic Research (ICA10-0098), the Board of Doctoral Education at Karolinska Institutet (JP), Engkvist's Foundations, Foundation Lars Hiertas Minne, Swedish Royal Academy of Sciences/Foundation Hierta-Retzius Fond, the Czech Science Foundation (13-32990S), the Program "KI-MU" (CZ.1.07/2.3.00/20.0180) co-financed from European Social Fund and the state budget of the Czech Republic and the Marie Curie ITN WntsApp (Grant no.608180; D.R. is funded by a postdoctoral fellowship from the Sven och Lilly Lawski Foundation (N2014-0049). Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC) and National Supercomputer Centre (NSC) in Linköping. J.C. and D.R. participate in the European COST Action CM1207 (GLISTEN). A.F. is supported by a grant from the Israel Science Foundation.

Publisher Copyright:
© 2017 The Author(s).


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